BT-11: A First-in-class Oral Therapeutic for Inflammatory Bowel Disease Biotherapeutics Inc (BTI) develops oral first-in-class therapeutics for autoimmune diseases. BT-11, a lead compound for treating inflammatory bowel disease (IBD), belongs to a new chemotype and targets the novel Lanthionine Synthetase C-Like 2 (LANCL2) pathway. BTI will file an IND for BT-11 in 18 months. Significance. IBD afflicts over 1.6 million Americans and 4 million people worldwide. An unmet clinical need for safer, more effective drugs remains, as current therapies have limited efficacy and adverse side effects. The Technology & Product. BTI validated LANCL2 as a therapeutic target for IBD and patented a novel chemotype, which encompasses 48 privileged scaffolds and >3 billion new chemical entities (NCEs), including BT-11, an orally active small molecule that binds to LANCL2 in the gastrointestinal (GI) tract. BT-11 has efficacy in 4 mouse models of IBD (8 mg/kg p.o.), has no toxicity in Ames and hERG screening, and has a benign safety profile in rats at doses up to 1,000 mg/kg p.o. The Specific Aims for the SBIR Fast-Track Phase I application are to: (1) Assess the therapeutic and prophylactic efficacy of oral, rectal versus intravenous (I.V.) BT-11 in the MDR1 mouse model of IBD. Using dose-response studies in the MDR1 mouse model of IBD, we will assess the efficacy of BT-11 in dose?response studies using three routes of administration. (2) Compare efficacy of BT-11 versus current drugs and INDs in the MDR1 mouse model of IBD. We will compare BT-11?s efficacy with standard-of-care drugs (5?ASAs, prednisone, azathioprine, and anti- TNF?) and INDs (anti-?4?7, anti-IL-12&IL23, tofacitinib, and GED0301). Transition Milestones are: Oral BT-11 outperforms current treatments by >30% in effects on inflammatory biomarkers and histopathological grading in the MDR1 mouse model of IBD. We provide preliminary data in MDR1 mice in support of being able to meet the transition milestones with BT-11 and do not anticipate any unforeseen challenges that prevent meeting the transition milestones.. The Specific Aims for the SBIR Fast-Track Phase II application are to: (3) Characterize the potential for human translation of BT-11 via cytokine profiling in ex vivo organotypic intestinal systems. We will use a novel organotypic human intestinal system (ileum and colon) to assess the effect of BT-11 on cytokine profiles in the gut from IBD patients. (4) Evaluate the distribution and toxicological profile of BT-11. We will perform dose-range finding (DRF) studies and in vitro genetic toxicology testing before moving to 8-week repeated dose toxicity GLP studies of BT-11 in rats as required for IND status. We will also identify potential off-target effects. Long-Term Goal: The goal of BTI?s LANCL2-based technology is to provide a first-in-class oral therapeutic for IBD that addresses an unmet clinical need for a market exceeding $7 billion and growing 25% annually.